Persistent Symptoms After the First Wave of COVID-19 in Relation to SARS-CoV-2 Serology and Experience of Acute Symptoms: A Nested Survey in a Population-Based Cohort

Many patients report persistent symptoms after COVID-19. Our aim was to determine whether some of these symptoms were more associated with past SARS-CoV-2 infection compared to other conditions.Methods: This prospective survey was nested in CONSTANCES, a randomly selected French population-based cohort, started in 2012. All participants being followed-up by internet completed 2 questionnaires during the first wave of the pandemic (April-March 2020) focusing on the acute symptoms of their COVID-19-like illness. Serological tests for SARS-CoV-2 were then performed (May-Nov 2020). Between December 2020 and January 2021, participants completed a third questionnaire about symptoms that had lasted more than 2 months. Participants were classified into four groups according to European Center for Diseases Control (ECDC) criteria for SARS-CoV-2 infection (ECDC+ or ECDC-) and according to serological SARS-CoV-2 test results (Sero+ or Sero-). To compare the risk of each persistent symptom among the groups, logistic regression models were adjusted for age, sex, educational level, comorbidities, and the number of acute symptoms declared during the first wave of the epidemic. A mediation analysis was performed to estimate the direct effect of the infection on symptom persistence and its indirect effect via the initial clinical presentation. Findings: The analysis was performed in 25910 participants. There was a higher risk of persistent persistent dysgeusia/anosmia, dyspnea and asthenia in the ECDC+/Sero+ group than in the ECDC+/Sero- group (OR: 6.83 [4.47-10.42], 1.69 [1.07-2.6] and 1.48 [1.05-2.07], respectively). Abdominal pain, sensitive symptoms or sleep disorders were at lower risk in the ECDC+/Sero+ group than in the ECDC+/Sero- group (0.51 [0.24-0.96], 0.40 [0.16-0.85], and 0.69 [0.49-0.95], respectively). The mediations analysis revealed that the association of infection with each symptom was mainly mediated by ECDC symptoms (proportion mediated range 50%-107%). Conclusion: After COVID-19, persistent symptoms are very similar to those after other similar clinical conditions, apart from greater risk of anosmia, fatigue and dyspnea. The acute clinical presentation drives the risk of persistent symptoms.Funding Information: The Constances cohort benefits from a grant from the French National Research Agency [Grant Number ANR-11-INBS-0002]: It is supported by the Caisse Nationale d’Assurance Maladie (CNAM), the French Ministry of Health, the Ministry of Research, the Institut national de la santé et de la recherche médicale. CONSTANCES and is also partly funded by MSD, AstraZeneca, Lundbeck and L’Oreal. The SAPRIS-SERO study was supported by Agence Nationale de la Recherche, #ANR-10- COHO-06, Santé Publique France : N°20DMIA014-0, Fondation pour la Recherche Médicale (#20RR052-00), Inserm (Institut National de la Santé et de la Recherche Médicale), #C20-26.Declaration of Interests: OR reports personal fees and non-financial support from ViiV healthcare, Gilead, MSD. CL reports personal fees and non-financial support from Boehringer Ingelheim, Janssen-Cilag, Lundbeck and Otsuka Pharmaceutical, outside the submitted work. The other authors declare that they have no competing interest.Ethics Approval Statement: Ethical approval and written or electronic informed consent were obtained from each participant before enrolment in the original cohort. The SAPRIS-SERO study was approved by the Sud-Mediterranée III ethics committee (approval #20.04.22.74247) and electronic informed consent was obtained from all participants for DBS testing